1,4-dihydro-4-oxo-2-quinazolinepropionic acid esters



United States Patent 3,499,897 1,4-DIHYDRO-4-OX0-2-QUINAZOLINEPROPIONIC ACID ESTERS Stanley C. Bell, Penn Valley, and Peter H. L. Wei, Upper wherein R is defined as above, X is halogen and R and R are lower alkyl. The reaction is efiected by contacting an appropriate 2 -carbalkoxy-3-halopropionanilide (I) with an alkali metal cyanide, e.g., sodium and potassium cyanide, and a lower alkanol at a temperature 1 2222,f ifigs ggfig sf g ggzgggi z gii gs g 5 range from about 60 C. to about reflux temperatures for No. Drawing. Filed Dec. 8, 1967, Ser. No. 688,984 a Perlod P abotlt i to about twenty-four h I t, CL an 51/4 erably this reaction 18 conducted with potassium cyanide US. Cl. 260-251 4 Claims at reflux temperatures for a period of about twelve hours.

When the reaction is complete, the resulting 1,4-dihydro-4-oxo-2-quinazolinepropionic acid ester (IV) is sep- ABSTRACT OF THE DISC OS RE arated by standard recovery procedures. For example, This invention concerns esters of the reaction mixture is filtered and the collected solid quinazolinepropionic acids which are pharmacologicany is recrystallized from a suitable solvent, e.g., an alkanol, 5 ace oni ri e an c oro orm. ompoun a -car active as mydriatic agents. t t l d f H d h alk0xy-3-cyanopropionanilide, is an intermediate in the preparation of the compounds of this invention which This invention relates to new and novel esters of h be separated from the mother fl of the reachhh quinazolinepropionic acids. In particular, this invention is mlxture by the Procedure exehlphfiefl 1h Example IL whlle concerned with 1,4-dihydro-4-oxo-2-quinazolinepropionic 20 the comPouhd (III) deplete? above reachoh acid esters which have mydriatic properties when tested cheme 1S a p t lhterrhedlate whlch has not f under Standard v acceptable pharmacological isolated but is herein included to elucidate the reaction cedures. They are, therefore, deemed to possess utility in mechahlshh of the above descnbhd prcfc'esh experimental and comparative pharmacology The 2 -carbalkoxy- 3-halopropionanill de (I) starting h new and novel compounds within the purview f compounds employed in the above described reaction may the present invention are illustrated by the following be Prepare"l1 by stahdard orgahlc procedhres Well known formula; to those skilled in the art of chemistry. For example, these H compounds may be prepared by reacting a Z-anthranilate with a B-halopropionyl halide. The new and novel 1,4-dihydro-4-oxo-2:quinazolinepro- R H CHQCHzCOzR pionic acid esters of the present invention possess val- N uable pharmacological activity. In particular, these compounds in standard pharmacological procedures demon- & strate mydriatic activity and are useful as mydriatic agents. Because of this property they are of importance wherein R is selected from the group consisting of hyin experimental and comparative Pharmacology f halogen lower alkyl and lhwer alkoxy; 3 R2 In the pharmacological evalution of the mydriatic com- 15 3 fy AS emplozed herelh the germs lower pounds of this invention the in vivo effects of the comalklfl and lower alkoxli Iheaht 9 Include both pounds of this invention are tested as follows: straight and branched chain moieties having from about The compound is administered Orally to the three mice S?ZiZ- %EiZET232352i ix'i tifilniiififiliififfi' gg an .m. eanimasarewace 0ramini ic acid, ethyl ester; 1,4-dihydro-7-methyl-4-oxo-2-quinazomum of two fi during which time Signs of general i z i il estlirl p z' ii' stimulation (i.e., increased spontaneous motor activity, $1,315 1Z1";013ELIiZSSZE EE FJEZSEH iiii beii l'esi i hyperaeflvity. on tactile Stimulation twitching) ea nated as 14-dihydro-4-oxo-2-quinazolinepropionic acids, depresslon ecreased spontalleous. lnotqr l l it Should i recognized that they also exist in their decreased respiration) and automatic activity (i.e.,miosis, tautomeric form as 3,4-dihydro-4-oxo-2-quinazolinepro. mydriasis, diarrhea) are noted. The animals are tested picnic acids for changes in reflexes (i.e., flexor, extensor) and are The Compounds f h present invention are syntherated by use of a pole climb and gnclined screen for the sized by the new and novel process which is hereafter Presence of sedatlon-ataxla- The Y' meth' schematically illustrated: 0d [Nathan B. Eddy and Dorothy Lelmbach, J. Phar- NHCOUH2CH2X NHCOCH2CH2ON R Substitution R R JR l Cyelizatiou C-CHz H t l "CHZCHQCOZRZ Rearrangement \CCH2 R1 l Ri I] N NH o= t a.

3 macol. Exper. Therap. 107, 385 (1953)] is used to test for analgesia. The experiment is terminated by subjecting each animal to a maximal electroshock to test for anti-convulsant activity.

The compounds of this invention in the above test procedure are autonomically active and produce mydriasis when orally administered at a concentration of 127 mg./kg.

The following examples are given by Way of illustration.

EXAMPLE I A solution of 23.6 g. of 2-carbethoxy-3,4-dichloropropionanilide and 5.9 g. of potassium cyanide in 200 ml. of 95 percent ethanol is heated to reflux overnight. The solid is collected (7.6 g.) Which is recrystallized from dimethoxy-ethane to afford 6-chloro-1,4-dihydro-4- oxo-2-quinazolinepropionic acid, ethyl ester, MP. 227-. 229 C.

Analysis.-Calcd. for C H ClN O (percent): C, 55.62; H, 4.67; Cl, 12.63; N, 9.98. Found (percent): C, 55.49; H, 4.66; C1, 12.7; N, 9.83.

Similarly, 7-bromo-1,4-dihydro-4-oxo-2-quinazolinepropionic acid, methyl ester and 6-fiuoro 1,4-dihydro-4-oxo- Z-quinazolinepropionic acid, propyl ester are also synthesized.

EXAMPLE II The solvent from the mother liquor of Example I is removed and the residue is first washed with water and a small amount of ethanol and finally recrystallized twice from cyclohexane to give 2-carbethoxy-4-chloro-3-cyanopropionanilide with a melting point of 11820 C.

Analysis.-Calcd. for C H ClN O (percent): C, 55.62; H, 4.67; CI, 12.63; N, 9.98. Found (percent): C, 55.77; H, 4.32; Cl, 12.4; N, 9.83.

EXAMPLE III A solution of 2-carbethoxy-3-chloro-5'-methyl propionanilide (0.08 m.) and potassium cyanide (0.09 m.) in 200 ml. of 95 percent ethanol is heated to reflux for twelve hours. The solid is collected and recrystallized from dimethoxyethane to afford 1,4-dihydro-7-methyl-4- oxo-2-quinazolinepropionic acid, ethyl ester.

In like manner, 6-ethyl-1,4-dihydro-4-oxo-2-quinazolinepropionic acid, methyl ester; 5-butyl-1,4-dihydro-4- oxo-2-quinazolinepropionic acid, butyl ester; and 1,4-dihydro-8-methyl-4-oxo-2-quinazolinepropionic acid, methyl ester are prepared.

EXAMPLE IV A solution of 2-carbethoxy-3-chloro-4-methoxy propionanilide (0.16 m.) and sodium cyanide (0.18 m.) in 400 ml. of propanol is heated to 80 C. for twenty-four hours. The solid is collected and then recrystallized from acetonitrile to aflord 1,4-dihydro-6-methoxy-4-oxo-2- quinazolinepropionic acid, propyl ester.

In the same manner, 7-ethoxy-1,4-dihydro-4-oxo-2- quinazolinepropionic acid, methyl ester and 6-butoxy-1,4- dihydro-4-oxo-2-quinazolinepropionic acid, ethyl ester are produced.

EXAMPLE V A solution of 2'-carbethoxy-3-bromo propionanilide (0.32 m.) and potassium cyanide (0.36 m.) in 800 ml. of

N TCHzCHzCOzRz wherein R is selected from the group consisting of chloro, bromo and fluoro and R is lower alkyl.

2. A compound as described in claim 1 which is: 6- chloro 1,4 dihydro-4-oxo-2-quinazolinepropionic acid, ethyl ester.

3. A process for the preparation of compounds having the formula:

wherein R is selected from the group consisting of hydrogen, halogen, lower alkyl and lower alkoxy; and R is lower alkyl; which comprises reacting a compound of the formula:

wherein R is defined as above and R is lower alkyl and X is halogen with an alkali metal cyanide and an alkanol of the formula:

R OH

wherein R is defined as above, at a temperature range from about 60 C. to about reflux temperatures for a period from about ten to about twenty-four hours.

4. A process as described in claim 3 wherein the alkali metal cyanide is potassium cyanide.

References Cited Bediet a1.: CA. 30, 6375 (1936). Yanai et a1: CA. 64, 11209b (1966). Kreicherga et al.: CA. 65, 169 14a (1966).

ALEX MAZEL, Primary Examiner R. V. RUSH, Assistant Examiner US. Cl. X.R. 260999, 309.7 

